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A Carbon Dioxide-Catalyzed Stereoselective Cyanation Reaction Tamal Roy, Myungjo Kim, Yang Yang, Suyeon Kim, Gyumin Kang, Xinyi Ren, Anders Kadziola, Hee-Yoon Lee, Mu-Hyun Baik, and Ji-Woong Lee ACS Catal., Just Accepted Manuscript • Publication Date (Web): 01 May 2019 Downloaded from http://pubs.acs.org on May 1, 2019
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ACS Catalysis
A Carbon Dioxide-Catalyzed Stereoselective Cyanation Reaction Tamal Roy,1 Myungjo J. Kim,2,3,‡ Yang Yang,1,‡ Suyeon Kim,2,3 Gyumin Kang,2,3 Xinyi Ren,1 Anders Kadziola,1 Hee-Yoon Lee,2* Mu-Hyun Baik2,3,* and Ji-Woong Lee1,* 1Department
of Chemistry, University of Copenhagen, Universitetsparken 5, Copenhagen Ø, 2100, Denmark of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Korea 3Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon 34141, Korea 2Department
ABSTRACT: We report an unprecedented Michael-type cyanation reaction of coumarins by using CO2 as a catalyst. The delivery of the nucleophilic cyanide was realized by catalytic amounts of CO2, which forms cyanoformate and bicarbonate in the presence of water. Under ambient conditions, CO2-catalyzed reactions afforded high chemo- and diastereoselectivity of -nitrile carbonyls, whereas only low reactivities were observed under Ar or N2. Computational and experimental data suggest the catalytic role of CO2, which functions as a Lewis acid, and a protecting group to mask the reactivity of the product, suppressing by-products and polymerization. The utility of this convenient method was demonstrated by preparing biologically relevant heterocyclic compounds with ease. KEYWORDS: Carbon dioxide• Cyanation • Cyanoformate • DFT calculation • Coumarins
The cyanoformate ion (NC-CO2-) is involved in the biological synthesis of ethylene at an Fe-containing enzyme (Figure 1a).1-2 And the formation of the cyanoformate ion from 1-aminocyclopropane-1-carboxylic acid is thought to protect the catalytically active Fe(III)-center, which may be poisoned by cyanide ligation.3-5 Although it is thermodynamically unstable, cyanoformate formed by combining cyanide and CO2 may present a new opportunity in synthesis as a convenient source of highly nucleophilic cyanides allowing to avoid the direct use of toxic hydrogen cyanide. Various surrogates of HCN are known, but they are based on forming HCN in situ.6 Recently, “shuttle” catalysis was introduced to deliver cyanide from less toxic alkyl nitriles.7-9 Nonetheless, cyanides are indispensable as reagents for many reactions. Inspired by the ethylene biosynthesis, we envisaged that the cyanoformate may be useful in organic synthesis. Combining cyanide and CO2 in solution affords cyanoformate spontaneously,5 as our experiments and calculations confirmed (Figure 1b), where the activities of the cyanoformate and bicarbonate remains uncovered. To investigate this hypothesis – a synthetic application of cyanoformate in chemical reaction - we chose coumarin derivatives. There are currently no convenient procedures for accessing nitrile derivatives of coumarins, which represent densely functionalized synthons for organic synthesis. Owing to the divergent reactivity of alkyl nitriles to amines, carboxylic acids, aldehydes/ketones, and amides, cyanation is ubiquitous in natural products syntheses, pharmaceuticals and polymers.1012 Hydrocyanation of unsaturated carbonyls is particularly interesting and results in -cyano adducts, which can be further elaborated to -aminobutyric acids and 1,2-dicarboxylic acids.13 However, 1,4-conjugate addition of hydrogen cyanide has been elusive due to the competing 1,2-addition reactions.14-15 Nagata and co-workers demonstrated that Lewis acids increased
selectivity toward 1,4-addition, but an aluminum-based reagent was necessary starting from gaseous HCN.16-17 a) Ethylene biosynthesis O NH2 H 2O HO (ACC) Asp OH 2 FeII O2, HCO3 His OH2 His ascorbate
b) Cyanoformate in a solution O2
Asp His
FeIII His
H2 N O
CN + CO2 O
CN + CO2 + H2O
e–, H+ His
OH
His
NCCO2 + H2O
C 2H 4
OH2
FeIII
K1 = 3.47 x 10–1 K2 = 1.56 x 10–3 K3 = 4.49 x 10–3
+ NCCO2 OH2 sequestration & decomposition
III
intact Fe c) This work CO2/HCO3H O
O
CO2 CN
Ph
O CN
K2 K3
CN + CO2
Asp
K1
O
CO2
Ph
water HO
CO2 (cat.)
NC
NCCO2 HCO3 + HCN HCO3 + HCN
G(sol) in DMF at 40 oC
• preventing oligomerization • activating electrophile
CO2H
NCCO2
• increasing CO2 concentration • carbonic acid formation
Ph
water
• facile ring-opening reaction • proton donor
Figure 1: a) Effects of cyanoformate in preserving the Fe(III) active center in the ethylene biosynthesis,5 b) DFT calculated equilibria and potential advantage of CO2 dissolution in cyanide and water containing solutions. c) Conjugate cyanation of coumarins.
Herein, we report an operationally simple 1,4-cyanation reaction of activated substrates, namely coumarins, to afford cyano carboxylates using CO2 and cyanide (Figure 1c). The presented reactions were highly chemo- and stereoselective even in the presence of water. A larger scale synthesis of -aryl-cyano esters demonstrates the utility of the protocol for preparing heterocyclic compounds. In-depth computational analysis supports the proposed catalytic role of CO2, bicarbonate and carbonic acid as Lewis- and Brønsted acids to selectively activate electrophiles. Recently, CO2-mediated organic reactions were reported18-20 expanding its role beyond the well-known function as a cheap C1 source.21-27 Fundamentally, adding CO2 to cyanide and using
ACS Paragon Plus Environment
ACS Catalysis it as a nucleophilic reagent is counterintuitive, as the nucleophilicity of cyanide is reduced upon forming cyanoformate.5 Nevertheless, we were surprised to obtain high isolated yield (90%) of 2a starting from coumarin 1a with high diastereoselectivity (20:1 dr) under CO2 atmosphere, whereas negligible reactivity was observed under N2 or argon atmosphere (Scheme 1). (A)
O
O
+
MeO
Ph
NEt4CN
1.2 equiv.
1a
(B)
OH CO2Me
CO2 (1 atm) ACN:DMF (1:1) 40 oC then MeI
MeO
Ph CN 2a, >15:1 dr
100
and Table S1). Catalytic amounts of NBu4Cl (10 mol%) was employed to evaluate a potential phase-transfer catalysis, but excess stoichiometric amounts of NBu4Cl (1.2 equiv.) was necessary to mediate the cyanation reaction (entries 9 and 10). Various Lewis and Brønsted acids, such as BF3-OEt2, Ti(OiPr)4, Sc(OTF)3, Fe(III), Cu(II), NH4Cl, HCl, with and without water showed negligible activity, implying a superior performance of CO2 and water in promoting nucleophilic cyanide addition reactions. To the best of our knowledge, this new reaction protocol employing tetraethyl ammonium cyanide with CO2 is the only method to selectively deliver cyanide for the conjugate addition reaction of coumarins. Table 1. Optimization of the reaction conditions.a
CO2
80
O
Ar
O
+ Ph
Yield (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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NEt4CN
1.2 equiv.
1b
60 40 20 0 0
20
40
60
80
100
120
Time (min)
Scheme 1. (A) Hydrocyanation and ring-opening reaction of coumarin 1a under CO2 and (B) a comparison of reactivities of 1a under CO2 (red) and argon (brown) as a function of time. Table 1 summarizes the optimization of reaction conditions based on the methyl ester of the ring-opened product (2b) in the presence of an internal standard. The structure of 2b was unambiguously confirmed by X-ray single crystal analysis (Scheme 2). The methylation of -cyano carboxylate intermediate was completely chemoselective without dimethylation.29 A control experiment with 13CO2 strongly suggested no incorporation of atmospheric CO2 in the final product (Figures S2 and S3).29 Reaction with D2O instead of H2O gave identical results (99% NMR yield, >15:1 dr) with >75% H-D exchange at both acidic protons on stereogenic carbons (Figure S6). Interestingly, small amounts of water (~1 vol%) improved the reaction rate, yield and selectivity toward the syn-product (entries 1 and 2), which may be due to water promoting the decomposition of cyanocarboxylate and faster release of cyanide.3 When the same reaction was carried out under nitrogen or argon atmosphere, only a trace amount (< 10%) of 2b was found with the majority of substrate remaining unreacted (entry 3). As a control experiment, a saturated solution was prepared purging a solution of tetraethyl ammonium cyanide with CO2. The use of this solution afforded 82% yield of 2b without additional gaseous CO2, confirming that the cyanation is feasible with dissolved CO2 (entry 4). Moreover, we tested reactions with reduced CO2 amounts (20 − 40 mol% with respect to coumarin 1b) and found up to 81% conversion 1b to the desired product, suggesting a potential turnover of CO2 (up to 3 TON, entry 5). Acetonitrile was a compatible solvent, however the diastereoselectivity was reduced to 6:1, while lower conversion was observed at room temperature (entries 6 and 7). Various insoluble cyanide sources were inferior to soluble ammonium cyanide (entry 8
OH CO2Me
CO2 (1 atm) DMF/water (100:1) 40 C then MeI
from
standard
Ph CN
2b, 90% (20:1 dr)
reaction
Yield (%)b
Entry
Deviation condition
1
none
99c (90)d
2
without additional water
90
3
argon or N2 instead of CO2
15:1 dr) compared to reactions under argon, where higher conversion was observed presumably due to stronger background reactions of alkyl substrates (see SI for more details). It is worth noting here that cyanation reactions under Ar generated unidentifiable byproducts including oligomers, which hampered isolation of the product. O
O
+
R1 R2
OH CO2R
CO2 (1 atm)
NEt4CN
1.2 equiv.
1a-s
DMF/water(1 vol%) rt to 40 oC, 0.5 - 12 h with/without MeI
OH CO2Me
R1
R2 CN 2/3a-s
OH CO2Me
MeO CN 2a, 90% (15:1 dr) argon:
